MATERNAL IMMUNE ACTIVATION DISRUPTS DOPAMINE NEURON ACTIVITY VIA MICROGLIAL COMPLEMENT CR3-DEPENDENT SYNAPTIC REMODELING

Maternal immune activation (MIA) during pregnancy increases offspring risk for neurodevelopmental disorders including autism and schizophrenia, which are associated with dopaminergic (DA) pathways abnormalities. MIA can be modeled in rodents by gestational exposure to polyI:C, a synthetic RNA mimicking viral infection. MIA offspring exhibit altered DA signaling, but the mechanisms involved remain unclear.
Here, we used polyI:C injections at gestational day 9 to model MIA in mice. We found that MIA reduced the frequency of excitatory, but not inhibitory, synaptic currents, and decreased dendritic spine density in ventral tegmental area (VTA) DA neurons. In vivo recordings revealed that VTA DA neurons in MIA offspring displayed decreased firing and reduced burst activity. These changes were accompanied by increased expression of complement protein C1q in the VTA. Because complement signaling regulates synapse remodeling via microglia, we tested whether microglia and the complement mediate these effects. Although microglial engulfment of Bassoon, a presynaptic protein, was unchanged, MIA increased microglial volume and branching complexity in the VTA in juvenile mice. Neonatal treatment with minocycline, an inhibitor of microglial reactivity, prevented MIA-induced synaptic, morphological, and DA neuron firing alterations. Similarly, MIA failed to alter excitatory inputs, spine density, or microglial morphology in mice lacking complement receptor CR3, which is specific to microglia in the brain parenchyma. Ongoing work is assessing whether CR3 deletion also protects against MIA-induced changes in DA neuron firing.
Together, these findings identify microglial reactivity and CR3-mediated complement signaling as essential mechanisms driving MIA-induced dysfunction of excitatory synapses and DA neuron activity.